Moody D E, Loury D N, Hammock B D
Toxicol Appl Pharmacol. 1985 May;78(3):351-62. doi: 10.1016/0041-008x(85)90240-6.
An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-alpha-(p-chlorophenoxyisobutyrate]. The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5%) and within a shorter time (5 days) than mEH and cGST (2%, 14 days) activity. After 14 days at 0.5% clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165% and 290, 220, and 75% of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.
用过氧化物酶体增殖性降血脂非基因毒性致癌物处理的小鼠肝脏中，胞质环氧化物水解酶（cEH）活性会增加。由于环氧化物代谢酶活性的增加可能反映致癌机制，因此已使用反式和顺式氧化芪这两种几何异构体作为底物，对用氯贝丁酯（乙基-α-(对氯苯氧基异丁酸酯)）处理的小鼠肝脏中cEH、微粒体环氧化物水解酶（mEH）和胞质谷胱甘肽S-转移酶（cGST）活性的反应进行了详细比较。cEH活性的最大增加出现在氯贝丁酯饮食剂量较低（0.5%）时，且比mEH和cGST活性（2%，14天）出现的时间更短（5天）。在0.5%氯贝丁酯处理14天后，雄性和雌性小鼠的cEH、mEH和cGST活性分别为对照值的250%、175%和165%以及290%、220%和75%。从饮食中撤去氯贝丁酯后，活性在7天内恢复到对照值。氯贝丁酯处理改变了所有三种酶活性的表观亚细胞区室化，可溶性与颗粒性活性的比值增加。特别是，所有三种酶的相对比活性在轻线粒体（过氧化物酶体）细胞组分中降低，而胞质中出现了类似mEH的活性（苯并[a]芘-4,5-氧化物和顺式氧化芪水解）。cEH活性的增加以及胞质中类似mEH活性的出现都是环氧化物代谢酶的新反应，这可能与氯贝丁酯处理、过氧化物酶体增殖、降血脂和非基因毒性致癌作用后的新细胞反应有关。
